Platinum (Pt) compound cis-diamminedichloridoplatinum(II) or cisplatin exhibits clinical activity against solid neoplasms of different kinds (Jamieson et al., Chem. Rev., 1999, 99:2467-2498; Jung et al., Chem. Rev., 2007, 107:1387-1407; Wang et al., Nat. Rev. Drug Discov., 2005, 4:307-320; Kelland et al., Nat. Rev. Cancer, 2007, 7:573-584; and Dhar et al., Bioinorg. Med. Chem. Wiley-VCH Verlag GmbH & Co. KGaA, 2011, pp 79-95). Initial success of cisplatin treatment regimen to originally sensitive tumor is often associated with chemoresistance (Kartalou et al., Mutat. Res., 2001, 478:23-43; and Siddik, Oncogene, 2003, 22:7265-7279), Colorectal, lung, and prostate cancers are also known to be intrinsically resistant to cisplatin-based therapies (Shen et al., Pharmacol. Rev., 2012, 64:706-721). Major side effects associated with cisplatin therapy are nephrotoxicity, peripheral neurotoxicity, and ototoxicity (Rabik et al., Cancer Treat. Rev., 2007, 33:9-23). However, the main limitation to cisplatin treatment is the high incidence of chemoresistance to escape this cytotoxic compound. Tumor cells develop a myriad of phenotypic changes by establishing a self-defense system, which include decreased cisplatin accumulation with a decline in Pt-DNA adduct, changes in gene expression levels associated with apoptosis, damaged DNA repair, chaperones, transporters, cell cycle arrest, protein trafficking, transcription factors, oncogenes, small GTPases, glutathione (GSH) and its related enzymes, cytoskeletal proteins, and mitochondria.
Further, aquation of cisplatin makes it activated towards the nucleophilic sites on the DNA for its anticancer activity. However, this activated form of cisplatin can also interact with other nucleophilic components, which include GSH and the cysteine-rich metallothionein in the cytoplasm. Thus, increase in such thiols will enhance inactivation and sequestration of cisplatin in the cytoplasm, reduce the availability of the antitumor agent in the nucleus to form DNA adducts, and induce resistance (Godwin, Proc. Natl. Acad. Sci. USA, 1992, 89:3070-3074; Kelland et al., Crit. Rev. Oncol. Rematol., 1993, 15:191-219; Kasherrnan et al. J. Med. Chem., 2009, 52:4319-4328). Studies indicated increased levels of detoxification enzyme (ISH-Stransferase-π, γ-glutamylcysteine synthetase (γ-GCS), and the transcription factor c-Jun in cisplatin resistance tumors (Peklak-Scott et Mol. Cancer Ther., 2008, 7:3247-3255; and Pan et al., Biochem. Pharmacol., 2002, 63:1699-1707). γ-GCS is involved in GSH biosynthesis, ATP-dependent glutathione Sconjugate export (GS-X) pump activity (Kurokawa et al., Cancer Science, 1997, 88:108-110; and Kurokawa et al., Jpn. J Cancer Res., 1997, 88:108-110). An increase in GSH is found in cisplatin resistance and the reaction between actuated cisplatin with GSH can happen either spontaneously or under catalysis by detoxification enzyme GSH-S-transferase-π (Goto et al., Free Radic. Res., 1999, 31:549-558 to form GS-Pt adducts (FIG. 1A). These GS-Pt adducts get excreted out from cells by GS-X export pumps. Additionally, the elevated GSH level contributes to cisplatin resistance due to increased Pt-DNA adducts repair, the capacity to suppress apoptosis by reducing reactive oxygen species (ROS) (Brozovic et al., Crit. Rev. Toxicol., 2010, 40:347-359). Metallothioneins also contribute to cisplatin resistance by deactivating the spontaneously agitated activated cisplatin using the thiol-containing cysteine residues (Kelley et al., Science, 1988, 241:1813-1815; Kasahara et al., Cancer Res., 1991, 51:3237-3242).
What are thus needed are new platinum containing anticancer drugs that can circumvent the resistance and side effects associated with cisplatin treatments. The compositions and methods disclosed herein address these and other needs.